Adrian Liston, Professor of Pathology at The University of Cambridge and Equalities Fellow at St Catharine’s College, shared a post on LinkedIn:
“A small primer on the Nobel Prize awarded to Brunkow, Ramsdell and Sakaguchi. This prize combined two fields of immunology research – genetic research on IPEX and immunology research of regulatory T cells (Tregs).
First, let’s talk IPEX. It is a severe autoimmune disease, impacting boys, which is fatal in early childhood unless treated. By coincidence, there was a mouse strain with the same disease and inheritance pattern called “Scurfy”. IPEX/Scurfy was rather mysterious, but because of the inheritance pattern it was quickly mapped to the X chromosome. Brunkow and Ramsdell led the teams that mapped this down to the FOXP3 gene in both humans and mice, with major papers in 2001.
Independent of this, we had the field of regulatory T cells. There were some misleading experiments on “suppressive T cells” early on, but the key were the papers of Nicole Le Douarin in 1987/1988. She grafted the wing buds of quail onto embryonic chickens, which were rapidly rejected by the immune system. The key finding was that if a proto-thymus was also transplanted the chickens kept their wings long term. This means that the chicken developed a form of tolerance mediated by T cells educated in the thymus but effective in the periphery.
It was a hard and unpopular field for decades, however, with the key pioneers being Fiona Powrie and Sakaguchi. They chased up independent sets of T cells with immunosuppressive properties, using different markers on what were ultimately the same cells – regulatory T cells, potent at shutting down immune responses in multiple different assays.
It wasn’t until 2003 that regulatory T cells gained wide uptake by the immunology community.
This key breakthrough happened by the linking of FOXP3, the IPEX/Scurfy gene, and regulatory T cells. Three groups, led by Sakaguchi, Ramsdell and Sasha Rudensky, all demonstrated that FOXP3 was acting as the master transcription factor that converted regular T cells into the immunosuppressive regulatory T cells. Suddenly everyone could study Tregs and manipulate their genetics, with tool after tool coming online (especially from Rudensky, Tim Spawasser and Jeff Bluestone). It triggered an exponential increase in papers on regulatory T cells, linking them to disease after disease.
The impact has been enormous, with regulatory T cells going from being a niche frowned-upon subset of immunology, to underpinning our entire understanding of how the immune system works. Therapies based on boosting Tregs (e.g. IL2) or bypassing Tregs (anti-CTLA4) have transformed treatments. The pre-clinical pipeline is even richer, so we can expect many more regulatory T cell-based therapies to enter the market soon!
Huge congratulations not only to the team leaders who won this prize, but all the students, technicians and expert scientists who did the work that underpins this discovery. Their work, and the work of those following in their footsteps, is changing the future for patients!”
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